CLINICAL-TRIALS OF MODULATION OF MULTIDRUG-RESISTANCE - PHARMACOKINETIC AND PHARMACODYNAMIC CONSIDERATIONS

A growing body of evidence indicates that expression of the mdr1 gene, which encodes the multidrug transporter, P-glycoprotein, contributes to chemotherapeutic resistance of human cancers. Expression of this pr otein in normal tissues such as the biliary tract, intestines, and ren al tubules suggests a role in the excretion of toxins. Modulation of P -glycoprotein function in normal tissues may lead to decreased excreti on of drugs and enhanced toxicities. A clinical trial of etoposide wit h escalating doses of cyclosporine (CsA) as a modulator of multidrug r esistance was performed. CsA was delivered as a 2-hour loading dose fo llowed by a 60-hour intravenous infusion, together with etoposide admi nistered as a short infusion daily for 3 days. Patients received one o r more courses of etoposide alone before the combined therapy to estab lish their clinical resistance to etoposide and to study etoposide pha rmacokinetics without and then with CsA. Plasma and urinary etoposide was measured by highperformance liquid chromatography and plasma CsA b y a nonspecific immunoassay. Conclusions from the initial phase I tria l with the use of CsA as a modulator of etoposide are: (1) Serum CsA s teady-state levels of up to 4800 ng/ml (4 mu M) could be achieved with acceptable toxicity. (2) Toxicities caused by the combined treatment included increased nausea and vomiting, increased myelosuppression, an d hyperbilirubinemia, consistent with modulation of P-glycoprotein fun ction in the blood-brain barrier, hematopoietic stem cell, and biliary tract. Renal toxicity was uncommon, but severe in two patients with s teady-state plasma CsA levels above 6000 ng/ml. (3) CsA administration had a marked effect on the pharmacokinetics of etoposide, with a doub ling of the area under the concentration-time curve as a result of bot h decreased renal and nonrenal clearance, necessitating a 50% dose red uction in patients with normal renal function and hepatic function. (4 ) The recommended dose of CsA is a 6-7 mg/kg loading dose administered as a 2-hour intravenous infusion followed by a continuous infusion of 18-21 mg/kg/day for 60 hours with adjustments in the infusion rate to maintain steady-state serum levels of 3000-4800 ng/ml (2.5-4.0 M). We are performing additional phase I trials combining CsA with single-ag ent doxorubicin and taxol, and the CsA analog PSC-833 with various mul tidrug-resistant-related cytotoxins.